Carbamazepine (5H-dibenz[b,f]azepine-5-carboxamide, CBZ), is a major drug used in the treatment of epileptic seizures and convulsions as well as in trigeminal neuralgia. However, in the treatment of epilepsy, approximately 25% of patients fail to respond to treatment. Furthermore, CBZ itself is associated with considerable adverse side effects, as described by L. Gram and P. K. Jensen in Antiepileptic Drugs, ed. R. H. Levy et al., Raven Press, N.Y. (1989), pages 555-565.
10-Oxo-carbamazepine (OCBZ) has been reported to be as active as CBZ, whilst exhibiting a smaller incidence of less severe side effects. It has been found to be of particular use in the treatment of patients suffering from generalized tonic-clonic convulsions and partial seizures with or without secondary generalization. The activity of OCBZ is attributed to its metabolite 10-hydroxy-10,11-dihydrocarbamazepine (DHOHCBZ); see M. Dam and P. K. Jensen in Antiepileptic Drugs, supra, pages 913-924.
Despite the favorable activity of these compounds, a drawback in their clinical use arises from their low solubility in aqueous media. It would be of considerable benefit if water-soluble derivatives of these compound existed and could therefore be administered intravenously. Such a route of administration would be especially beneficial in the treatment of Status Epilepticus. Water-soluble formulations of CBZ and OCBZ have been described in European Patent Applications, Publication Nos. 400609 and 435826, both of Ciba-Geigy. These formulations are obtained by formulating the drugs with cyclodextrin derivatives.
Another difficulty with the prior art is the lack of an efficient and inexpensive preparation of DHOHCBZ. Several routes have been proposed. For example, DHOHCBZ has previously been prepared by hydrogenating OCBZ under high temperature and pressure as described in U.S. Pat. No. 3,637,661 of Ciba-Geigy. Reduction by NaBH.sub.4 of the keto functionality in the benzo{b,f}-azepine series has been described for the 10-oxo-11-acetate derivative of CBZ (see R. Heckendorn, Helv. Chim. Acta (1987) 70, 1955, 1956) and for 10-oxo-5-dialkyl-aminoalkyl derivatives in U.S. Pat. No. 3,185,679 of Geigy.